Pakistan speedster Mohammad Irfan tore through the top order and South Africa were restricted to a modest 191 which the tourists passed with more than four overs to spare in a game that had been reduced to 44 per side by a rain delay.
Misbah shared a match-winning unbeaten fifth-wicket stand of 77 with Shoaib Malik (35 not out) as the pair showed patience initially and then blasted their way to victory.
Younus Khan (32) and Mohammed Hafeez (31) also made valuable contributions in a low-scoring game, but the win was set up by an attacking display with the ball.
Irfan posted career best figures of four for 33 as he took full advantage of the pace and variable bounce in the wicket.
He helped reduce South Africa to 62 for five before a fighting maiden one-day international half-century from Farhaan Berhardien (58) and a career-best 44 from Robin Peterson gave the hosts a glimmer of hope.
"The way we started, four wickets in the first 10 overs, that set up the game for us," Misbah said in a television interview.
"It is satisfying for us because we really needed this win. It was an attacking move to bring in Mohammad Irfan and it paid off for us."
Pakistan paced their chase expertly and South Africa's frustration led to a wayward bowling performance.
They offered Pakistan far too many opportunities to score and battled to create any pressure.
"It was a very disappointing performance, Pakistan took the initiative early on and bowled very well," captain AB de Villiers said.
"There are no excuses, we just didn't play well today. They controlled the game and did it easily in the end."
The teams head into Sunday's third one-day international with the series level at 1-1 after South Africa had breezed to a 125-run victory in the first match in Bloemfontein last weekend.
- Sports & Recreation
- South Africa
- Mohammad Irfan